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Follicular lymphoma cells tend to grow in a circular pattern and replace the normal structure of a lymph node. The disease is often slow-growing but hard to cure.

Summary

A gene called KMT2D is mutated in at least half of all follicular lymphoma tumors. A surprising discovery reveals that this gene does not directly drive uncontrolled cell growth, but instead controls the activity of hundreds of other genes through a process called epigenetic regulation. Understanding the molecular cause is an important step toward new and better therapies for this common, incurable form of non-Hodgkin lymphoma.

Highlights

Follicular lymphoma has remained incurable.

A gene called KMT2D is frequently mutated in this disease.

Research shows how this mutation leads to uncontrolled cell growth.

This is an important step toward more effective therapies.

Over the past few decades, there has been little progress in developing new therapies for follicular lymphoma, one of the most common forms of non-Hodgkin lymphoma. The disease, which involves the abnormal production of white blood cells called B cells, is often slow growing but is still considered incurable. It also has proven hard for researchers to study, due to a lack of cell lines and a good animal model.

Now Memorial Sloan Kettering researchers led by cancer biologist Hans-Guido Wendel, working in collaboration with the laboratory of Ari Melnick at Weill-Cornell Medical College, have made a surprising discovery about the molecular basis of follicular lymphoma. The most commonly mutated gene in this disease, KMT2D, does not cause cancer through the typical mechanisms, which act directly to drive uncontrolled cell growth. Instead it controls the activity of hundreds of other genes through a process called epigenetic regulation.

[KMT2D] is the most important mutation in this incurable disease.

Hans-Guido Wendelcancer biologist

“This is the most important mutation in this incurable disease, and we figured out what it does,” says Dr. Wendel. “Understanding the molecular cause is an important step toward new and better therapies. For example, emerging drugs are able to target some of these signaling pathways and may be effective against these tumors.”

A Mutation’s Ripple Effect

Epigenetics relates to a gene’s functioning being changed by factors unrelated to the sequence of its DNA. Epigenetic changes are a normal part of many biological processes, but they also can lead to cancer and other diseases.

KMT2D operates through an epigenetic mechanism called histone modification. Histones are proteins that DNA wraps around like yarn on a spool. In effect, if the DNA is wrapped too tightly, it is unable to unspool and the genes encoded on it cannot be expressed — they remain “off.” If it’s too loose, genes that should remain silent may be activated.

When the KMT2D gene is mutated, other genes fail to switch on.

Ana Ortega-Molinapostdoctoral fellow

The tightness or looseness of the DNA — and resulting gene expression — is regulated by histone modifying enzymes, or HMEs, which “mark” a histone to alter it. The KMT2D gene produces an HME that uses this process to turn on an array of genes that manage B cell growth and prevent the cells from becoming malignant.

“We found that the KMT2D enzyme activates a large number of genes, many of which are essential to the normal production of B cells,” explains Ana Ortega-Molina, a postdoctoral research fellow in Dr. Wendel’s laboratory and one of the first authors of the study. “When the KMT2D gene is mutated, these other genes fail to switch on, and the B cells don’t receive the signal to stop dividing when they should. This results in the proliferation of abnormal B cells that leads to follicular lymphoma.”

A Better Tool Provides the Proof

KMT2D is one of the most frequently mutated genes across all cancer types. This is especially true for follicular lymphoma — at least 50 percent of tumors have KMT2D gene mutations.

The frequency of these mutations indicates that this is likely one of the key causes of the cancer and makes KMT2D an inviting target for study. However, until recently it was difficult to design a way to clarify its normal function — and to figure out how the breakdown of that function could cause the disease.

A key step forward was the Wendel lab’s development of a follicular lymphoma mouse model in 2011. This tool is now broadly used by scientists working on lymphoma and allows researchers to conduct experiments clarifying the function of specific genes mutated in follicular lymphoma cells and to test new therapies.

A mutation in KMT2D – a gene that controls the activity of hundreds of other genes, including those responsible for suppressing tumors – is implicated in at least 50 percent of follicular lymphoma cases. Shown here: the enzymatic activity of KMT2D along the tumor suppressor Tnfaip3 is significantly weaker in tumors with a mutation in the KMT2D gene (red) compared to that of tumors without the mutation (black).

In the Nature Medicine study, Dr. Ortega-Molina used this model to test what happened when KMT2D activity is blocked. She found that loss of the enzyme’s function caused the mice to develop more advanced follicular lymphoma tumors even more rapidly, demonstrating a functional link between the gene mutation and the disease.

Genetic analysis of the tumors allowed her and her collaborators at Weill-Cornell to define exactly how the mutations lead to cancer and which genes are directly affected when KMT2D is mutated.

“Ana is the first person to show that KMT2D acts as a tumor suppressor through epigenetic regulation of critical growth and survival pathways in B cells,” Dr. Wendel says.

He adds that clarifying KMT2D’s role could guide new treatment strategies. “We know that mutation of KMT2D leads to loss of a specific mark on histone proteins,” he explains. “We also know which other genes are responsible for removing this mark as part of their normal function. We can speculate that inhibitors of these removal factors may restore the balance and could be effective against lymphomas caused by mutated KMT2D.”

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Comments

BethAnn

Sep 24, 2015 • 6:11 PM

My brother and I both have fnhl. He was stage IV at diagnosis and I was stage III. We are 13 months apart in age (I am younger) and they found my cancer first. I wanted to know if there are any sibling studies to look at this mutation?

I am a registered nurse and a follicular NHL patient. Looking forward to reading remission!

Anonymous

Sep 27, 2015 • 1:06 AM

Supposing that the tumor growth in follicular nhl is due to said genetic mutations, how effective could a stem cell transplant be? I've already had r-chop and r-epoch treatments. It has been suggested that a stem cell transplant would be the next possible course of treatment. I don't see how it would correct dna mutations though.

Thank you for reaching out. We suggest you discuss your treatment options, including a possible stem cell transplant, with your treating physician, as every individual case is different.

If you would like to make an appointment with a Memorial Sloan Kettering physician, please call our Physician Referral Service at
800-525-2225 or go to http://www.mskcc.org/cancer­care/appointment. Thanks for your comment.

AJohn Nonymous

Sep 27, 2015 • 12:28 PM

I have stage 2 follicular lymphoma.My oncologist is prescribing retuxen, I would like to know the success rate of this treatment.

Phil, thank you for reaching out. Research is still ongoing and it is not clear what causes follicular and other non-Hodgkin's lymphomas. For more information, you might contact the National Cancer Institute’s Cancer Information Service at 800­4CANCER (800­422­6237). To learn more about the CIS, including Live Chat help and how to send them an email message, go to http://www.cancer.gov/aboutnci/cis/page3.

Hilary Harmon

Sep 28, 2015 • 6:46 PM

Nancy, I agree. I am also a RN with FNHL and would love to hear the word remission. Thank you leukemia and lymphoma society for the life saving research you support! And Kettering Sloan for the research you do!

Anonymous

Sep 28, 2015 • 8:23 PM

I was just diagnosed today with follicular lymphoma from the results of a biopsy of my forehead. I am scheduled to see an oncologist tomorrow. I read that this is an incurable disease. What are the basic treatment options and the normal life expectancy. I am in my mid 50s. Thank you.

Thank you for reaching out. We consulted with MSK medical oncologist Anas Younes, who responded: "The most important thing is to confirm the diagnosis, and then determine the stage (extent of disease). Stage assessment is done by CT scans, PET scan and bone marrow biopsies. Depending on the final diagnosis and stage of the lymphoma, the treatment, prognosis, and cure rate vary significantly."

Carol

Sep 28, 2015 • 9:55 PM

my husband was diagnosed in 2012 with stage 4 nfl and has been in remission since Rchop chemo for 3 years. Is this a good sign that it may not return?

Carol, this is something you should discuss with your husband's healthcare team. If you'd like to make an appointment for a consultation at MSK, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment.

Heather

Oct 3, 2015 • 2:54 AM

How can patients be tested for this gene mutation? It would be good to know should clinical trials open that address this specific issue. Thanks!

Heather, thank you for reaching out. The mutation in KMT2D (also referred to as MLL2) is tested for by the MSK-IMPACT panel at Memorial Sloan Kettering. In order to take advantage of this type of molecular testing you would need to make an appointment with one of our specialists. To do so, please call our Physician Referral Service at 800-525-2225.

You also might contact the Cancer Genetics Inc, which may make a test for this mutation available through your oncologist:

I have completed 6 monthly treatments of Rituxan Bendamustine to treat Follicular Lymphoma. Complete response! Now Rituxan maintenance every 3 months for 2 years. On relapse what is the best strategy? If transformation to DLBCL what is the best strategy?

Peter, we recommend that you discuss this with your healthcare team. If you'd like to make an appointment for a consultation at MSK, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment.

Smd

Oct 16, 2015 • 8:46 AM

Hi I have a dear friend dx with nfl stage 3...and oncologist just want to watch it grow for 3 months...why????? So frustrating!!!

Unfortunately, we are unable to answer specific medical questions on our blog. If your friend would like to make an appointment with a Memorial Sloan Kettering physician for a consultation, he or she can call our Physician Referral Service at 800-525-2225 or go to http://www.mskcc.org/cancer­care/appointment. Thanks for your comment.

Cathy Morris

Oct 16, 2015 • 4:38 PM

I was initially dx in 2008 FNHL stage IV with 100% bone marrow involvement. I've been through R-CHOP, ESHAP, Bendamustine, auto SCT, 22 rounds of radiation on a spinal tumor between T11 & T12 and finish a 12 course regiment of Revlimid. With being adopted with no family history it would be amazing to see what comes from this study. Keep up the great work!!

Roger

Oct 28, 2015 • 2:41 PM

I support my wife who was diagnosed with FL in 2008. This article began with a statement I strongly disagree with: "Over the past few decades, there has been little progress in developing new therapies for follicular lymphoma". Since 2008 there are so many new treatment choices available that it makes this the toughest decision of all. Not that long ago there were no MAB's, bendamustine, inhibitors or blockers. Anyway, keep up the great work LRF!

Anonymous

Oct 28, 2015 • 3:26 PM

Since genes are involved is there a suggestion that there could be a hereditary factor here? If so should the young children of a diagnosed nhfl patient be tested now and during their lives as a preventative measure and if so, how early can it be detected? Thank you to everyone for your ongoing work of this disease.

Thank you for your question. Research is still ongoing and it is not clear what causes follicular and other non-Hodgkin's lymphomas. For more information, you might contact the National Cancer Institute’s Cancer Information Service at 800­4CANCER (800­422­6237). To learn more about the CIS, including Live Chat help and how to send them an email message, go to http://www.cancer.gov/aboutnci/cis/page3.

Mikki

Oct 28, 2015 • 3:28 PM

Your responses to most postings are: "Thank you for reaching out." followed by "ask someone else or make and appt. with us." Please don't respond in this manner to my question: I was diagnosed stage IV FL with bone marrow involvement 2010. Several treatment cycles of Rituxan and Bendamustine were ineffective. Have no evidence of cancer after R-CHOP. Clear for 1.5years. When it comes back, what are the possible next treatment choices? I said "possible", so not asking for a definitive answer. Just what is left out there after Rituxan, Bendamustine, and R-CHOP?

Dear Mikki, we are sorry to hear about your diagnosis. We don't know a commenter's full medical history so we cannot say with certainty which treatment options would be appropriate. Only a person's oncologist can make specific recommendations. Having said that, there are excellent resources where you can learn more about various treatment options available for people with recurrent follicular lymphoma and discuss them with your physician:

I had a stem cell transplant from an unrelated donor in 2007 at Seattle Cancer Care Alliance, Seattle, WA. Eight years later, I am pleased that I continue to be cancer free. I was diagnosed with stage 4 NHFL in 2004 and was treated at Swedish Cancer Institute with R/Chop, Rituxen. My cancer returned agressively in 2006 and after another round of R/Chop, Rituxen and ICE at Swedish, I was referred to SCCA. I can highly recommend SCCA to anyone considering a stem cell transplant.

Anonymous

Oct 28, 2015 • 4:08 PM

Wow!! This is great news. I am a male diagnosed with stage 4 FL and 25% bone marrow involvement. I have had no symptoms and just elected for 4 doses of ritux. My scans showed 25-50% shrinkage. My oncologist advised to go back to watch and wait, is there any benefit to keep going until it clears?

Thank you for reaching out. We recommend you discuss this with your oncologist, as every person's medical case is different.

Anonymous

Oct 28, 2015 • 5:13 PM

Anon 4:08 pm congratulations of your positive results. I was diagnosed with fNHL in 2008, and had Rituxan + Bendamustine in 2011. My first post treatment scan showed a small mass remaining (abdominal) but my 1-year CT scan showed nothing -- 100% response. My last scan was in 2013, I am symptom free. My next scan is in April '16. I hope you continue to do well and feel well.

Nadine

Oct 28, 2015 • 6:38 PM

In 2003 I was diagnosed with stage 3 indolent, follicular NHL. No bone marrow involvement. Non symptomatic except two hard nodules on either side of neck by the shoulder. I was given the mildest chemo fluradurbine. It came back in 2004 and then I got the big stuff. R-chop. with follow up Rituxan. I have been in remission since then. I go to oncologist every 6mts. Last visit he said to come back in a yr. I feel very blessed and lucky, and felt all the survivors out there need to here good news. Thank you LRS for all the work you do.

John Simmons

Nov 5, 2015 • 3:44 PM

I am 47 and diagnosed with fl, stage 3 earlier this year. I wait and see -and search the internet for breaking news like this.
What would you recommend me to do with this article? Shall I ask my hematologist to read it? PS I live in The Netherlands, Europe.

John, thank you for reaching out. We recommend you continue consulting with your hematologist about your best treatment options. The finding described in the story was made in the laboratory and it is difficult to predict when it might have clinical impact.

If you are interested in coming to Memorial Sloan­Kettering for a consultation or having your records reviewed, you can contact our International Center by calling 1­212­639­4900 or going to http://www.mskcc.org/cancer­care/international­patients. The email address is international@mskcc.org.

Christine Bitz

Nov 15, 2015 • 12:15 AM

I was diagnosed in 2009 with Follicular Lymphoma. I receive CVP with Rituxin and am now cancer free. Is it recommended or an advantage to test for the KMT2D by having the MSK-IMPACT panel? Or is it best to have this test before you are diagnosed? Thank-you

Christine, currently MSK-IMPACT is available to our patients with advanced disease. If you are in remission, it's not something that would be used at this time. We're glad to hear you're doing well. Thank you for your comment.

Allen Bourne

Nov 27, 2015 • 7:28 PM

Take heart, fellow FL patients; there are promising developments in treatment. A CT scan following an accident in a taxi revealed I had FL, stage 1, no bone marrow issues. I qualified for trial of rituxan (four treatments) and daily (to date) oral treatment with ibrutinib. Within three months there were no signs of active cancer and lymph nodes had decreased in size roughly 80%. I'm now about 18 months from beginning the regimen and remain in remission. The folks at MSK are right; every situation is different, but there is a lot happening in this area for you to anticipate.

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We welcome your questions and comments. While we share many of them with our world-class doctors and researchers, we regret that in order to protect your privacy, we are not able to make personal medical recommendations on this forum, nor do we publish comments that contain your personal information. If you would like to consult with an MSK doctor, we encourage you to make an appointment at 800-525-2225 or request an appointment online.

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